Biology Reference
In-Depth Information
renal cell carcinoma, and melanoma (Kemeny
et al.
, 1990, Rinehart
et
al.
, 1990). As mentioned above, TNFα recruits other cytokines such as
IL-2 and IFN-γ, and through a complex immune mediated pathway,
tumors are disrupted and eliminated. The results of much research
support the conclusion that TNFα causes hemorrhagic tumor necrosis
through angiogenic endothelial cell apoptosis. Current thinking favors
the point of view that TNFα deactivates an important adhesion receptor
in tumor angiogenesis, integrin α
v
β
3
, which results in a lethal disturbance
of the neovasculature. Integrin α
v
β
3
is a continuously active integrin that
anchors endothelium cells to the extracellular matrix proteins (ECM). It
is essential for neovasculature endothelial cell survival. Altering the
α
v
β
3
-dependent adhesion of endothelial cells to the ECM proteins causes
eventual cell death (Ruegg
et al.
, 1998, Havell
et al.
, 1988). The
damaged endothelial cells are then destroyed by T cells. Since integrin
α
v
β
3
is only expressed in neovasculature, normal vasculature remains
unaffected. TNFα is also known to increase vascular permeability and
reduce interstitial fluid pressure within the tumor, allowing easier
penetration of anticancer drugs into the tumor site (Folli
et al.
, 1993,
Kristensen
et al.
, 1996).
This latter effect may partly explain why several
chemotherapeutic drugs such as the alkylating agent melphalan (
4
, see
Fig. 6.3), marketed as Alkeran, act synergistically with TNFα.
Unfortunately, despite these encouraging findings on the potential
for fighting cancer, the adverse effects of systemic TNFα production are
too overwhelming to permit its use as a general anticancer therapy. It
has been reported that humans can only tolerate about 2 percent of the
dose/kilogram needed in mice for tumor regression (about 50 mg/kg)
(Spriggs and Yates, 1992, Sidhu and Bollon, 1993). Direct TNFα
infusion also has been unsuccessful because the plasma half-life of
TNFα is about 15 minutes in humans, insufficient time for complete
removal of a tumor (Blick
et al.
, 1987). Under these circumstances, the
injected cytokine only causes a transient increase in the host's response
before it is cleared by the liver or kidney.
It became clear that localization of the cytokine around the tumor
would be the most viable approach to effective and safe treatment.
Localized application of TNFα has taken several forms, mostly relying
on linking the cytokine to some sort of tumor-selective delivery vehicle.
